Immune activation induces activation and maturation of dendritic cells. Dendritic cells (DCs) are a part of the immune system that act as antigen-presenting cells. They process antigen material and present it on their cell surface. The antigen material may be from microbial organisms such as viruses or bacteria or from self antigens.
Immature DCs become activated after detecting a microbial antigen. The antigen protein is degraded by DCs and the fragments are presented on their surface in association with Major Histocompatibility (MHC) molecules. Upon activation, DCs migrate to the lymph nodes and present these antigens to T lymphocytes. This is the first step of the adaptive immune response.
Cancer immunotherapy aims at eliciting an immune response directed against tumor antigens. One approach is through vaccination by the provision of an antigen together with an adjuvant to elicit therapeutic T cells in vivo. DCs have been used in this context due to their high antigen presenting property, which makes them the natural agents for tumor-associated antigen delivery. In particular, ex vivo generated DCs can be loaded with antigens and re-infused to the patient. Alternatively, antigens can be targeted to DCs in vivo without need for ex vivo cell manipulations (Palucka & Bachereau, Nat Rev Cancer, 2012, 12, 265; Tacken et al, Nat Rev Immunol, 2007, 7, 790). However, one limitation is that the DCs injected to patients migrate inefficiently to lymphoid organs, a process required to trigger antitumoral immunity.
DCs have several functions in innate and adaptive immunity. In particular, there is increasing evidence that DCs induce antigen-specific unresponsiveness or tolerance in central lymphoid organs and in the periphery. In particular, immature DCs induce tolerance either through T cell deletion or by inducing the expansion of regulatory and/or suppressor T cells. Accordingly, they have tolerogenic properties that can be used in the treatment of autoimmune diseases such as diabetes, arthritis and autoimmune myocarditis (Steinman et al, Annu Rev Immunol, 2003, 21, 685-711; Xiao et al, J Immunother, 2006, 29, 465-471; van Duivenvoorde et al, J Immunol, 2007, 1506-1515; Valaperti et al, Vaccine, 2013, 31, 4802-4811; Tbarozzi et al, Clin Exp Immunol, 2012, 171, 135-146). Therefore, in this context, it might be advantageous to enhance the migration of DCs to the lymph nodes, in particular of immature DCs.
DCs are not the only cells for which migration is essential. Indeed, cell migration is a central process for embryonic development, wound healing, and metastasis.
An understanding of the mechanism by which cells migrate may lead to the development of novel therapeutic strategies for controlling, for example, invasive tumoral cells. For instance, invasion into the lymphatic system allows the transport of tumor cells to regional and distant lymph nodes and, ultimately, to other parts of the body. Cancer cells may spread to lymph nodes near the primary tumor and then disseminate. This is the most common route of metastasis for carcinomas. Therefore, it might be advantageous to decrease or prevent cancer cell migration in order to avoid metastasis. However, attempts to prevent cancer spreading by inhibiting cell migration have not succeeded so far.
Interestingly, cancer cells share migration properties with DCs. More particularly, podosomes or invadosomes are cylindrical, actin-rich structures that display a polarized pattern of distribution in migrating cells. Their primary purpose is connected to cellular motility and invasion. Many different specialized cells exhibit these dynamic structures such as invasive cancer cells, and certain immune cells such as DCs (Gimona et al, Current Opinion in Cell Biology 20 (2): 235-41).